Project Summary Neurodegenerative disorders, such as Alzheimer's Disease and Parkinson's Disease, are major health issues world-wide. The role of glia in neurodegeneration is not well understood, and the role may differ depending on the specific type and stage of disease. A major function of glia during brain homeostasis is the phagocytosis of pruned axons, dead or injured cells, and debris. Several lines of evidence suggest that glial phagocytosis plays an important role in the prevention or progression of brain disorders, including neurodegenerative diseases. In this proposal, we investigate the role of phagocytosis in neurodegenerative disorders using the model organism Drosophila melanogaster. Drosophila provides a wealth of genetic and cell biological tools for the study of glial phagocytosis and neurodegeneration. Several human neurodegenerative disorders have been modeled in Drosophila, providing a powerful platform for screening for genetic interactors. Moreover, the genes controlling phagocytosis are largely conserved between flies and mammals. Recently, we have shown that a disruption of the phagocytic receptor Draper in glia leads to persisting neuronal corpses and neurodegeneration in Drosophila. Here we will examine whether persistent corpses or debris in the draper mutant brain lead to neurodegeneration by triggering inflammation. We will additionally determine how loss of Draper interacts with genetic models of Alzheimer's disease, and investigate the role of inflammation in these disease models. Phenotypes will be analyzed by molecular, cellular and behavioral assays. These findings will provide insight into the impact of defective phagocytosis in neurodegenerative disorders.